Viral hemorrhagic fevers (VHFs) refer to severe multisystem syndrome, caused by viruses of four distinct families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. These symptoms are often accompanied by hemorrhage (bleeding). While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. Currently, there is no treatment or established cure for VHF infection. Ribavirin, an antiviral drug, has been effective in treating some individuals with Lassa fever or hemorrhagic fever with renal syndrome (HFRS). Treatment with convalescent-phase plasma has been used with success in some patients with Argentine hemorrhagic fever.
In the search for new anti VHF viruses, researchers have tried using nucleosides as inhibitors of dengue virus (Zheng Yin, et al, PNAS 2009, 20435-20439), kinase inhibitors for inhibition of Lassa virus and Ebola virus infection (Andrey Kobokoltsov, Arch Virol 2012, 121-127), acridone derivatives as inhibitors of Junin virus RNA synthesis (Claudia Sepulveda, Antiviral Res. 2012, 16-22). However, these approaches have met with limited success. Thus, there is a long felt need for new antiviral drugs that are both disease-modifying and effective in treating patients that are infected viral hemorrhagic fever (VHFs) viruses.
One approach to developing antiviral compounds is to design a molecule targeting host factors that are essential for the virus life cycle, thereby providing antiviral effect. In theory, by targeting host pathways used in common by all the hemorrhagic fever viruses, it should be possible to discover broad spectrum antiviral agents. If the viruses are more dependent upon the host pathway than is the host, selectivity and a useful therapeutic is possible. Viral hemorrhagic fevers (VHF) viruses each contain different RNA genomes, but they are all enveloped with glycosylated viral proteins and share a similar morphogenesis strategy of budding, which would make them sensitive to glucosidase inhibitors. This is presumably because the folding of N-linked glycoproteins in these viruses depends upon calnexin, a chaperon that folds proteins that have been trimmed by the Endoplasmic reticulum (ER) glucosidase. Most cell functions can compensate for a reduction in glucosidase enzyme function; however, the calnexin dependent viral envelope proteins cannot apparently use alternative processing pathways. Thus, glucosidase inhibitors would be selective antiviral agents against multiple enveloped viruses.
Imino sugars, such as deoxynojirimycin (DNJ) and its derivatives have been found glucosidase inhibitors. Despite great potential as broad-spectrum antivirals, clinical development of imino sugars has been limited by their low efficacy. The glucosidase inhibitors, N-butyl-DNJ (NBDNJ) currently approved by the US and European FDAs for use in the management of Gaucher's disease and Cellgosovir (in Phase II human trials for Hepatitis C virus infection), both require near millimolar concentrations to achieve EC50 values in tissue culture against their target viruses. NBDNJ has been dropped for antiviral development, due to the failure to achieve therapeutic concentration in vivo. Thus, there remains an urgent and unmet need for glucosidase inhibitors useful as antiviral agents.
The present invention addresses the need for new antiviral drugs that are both disease-modifying and effective in treating patients that are infected with viral hemorrhagic fever (VHFs) viruses. The present invention also addresses the long felt need for new treatments for and means of preventing diseases that involve viral infection and other diseases that involve glucosidase activity.